Potassium Fluoride → tert-Butyl 3-(3-carbamoylphenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate

Temperature

70 °C

To a 250 mL flask was added 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (20 g, 56 mmol), 3-carbamoylphenyl boronic acid (10.2 g, 61 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (2 g, 2.2 mmol), tricyclohexylphosphine tetrafluoroborate (PCy3HBF4) (1.65 g, 4.4 mmol) and KF (9.8 g, 168 mmol). The reagents were purged with nitrogen for 5 min, and then THF (120 mL) and DMF (30 mL) was added. The suspension was stirred and purged with nitrogen for another 5 min, then heated to 70° C. After 2 h at 70° C., the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was partitioned between EtOAc (350 mL) and 0.5 N NaOH (400 mL)/brine (50 mL). The organic layer was separated and dried with Na2SO4. A quarter of the solution was removed. The remainder of the solution was concentrated to ˜100 mL to which hexanes (50 mL) was added. Solid precipitates were observed. The solution volume was reduced by 10 mL, hexanes (10 mL) was added, and the slurry was stirred at 0° C. for 1 h. The solids were filtered and dried to give the title intermediate (8.4 g) as light yellow solids. The mother liquor was further concentrated to give more solid precipitate, which was filtered to provide additional product (0.5 g). (Combined 66% yield).

1. customThe reagents were purged with nitrogen for 5 min
2. additionTHF (120 mL) and DMF (30 mL) was added
3. custompurged with nitrogen for another 5 min
4. temperaturethe mixture was cooled to room temperature
5. filtrationfiltered through Celite
6. concentrationThe filtrate was concentrated
7. customthe residue was partitioned between EtOAc (350 mL) and 0.5 N NaOH (400 mL)/brine (50 mL)
8. customThe organic layer was separated
9. dry with materialdried with Na2SO4
10. customA quarter of the solution was removed
11. concentrationThe remainder of the solution was concentrated to ˜100 mL to which hexanes (50 mL)
12. additionwas added
13. customSolid precipitates
14. additionwas added
15. stirringthe slurry was stirred at 0° C. for 1 h
16. filtrationThe solids were filtered
17. customdried

ORD record

ord-1e8d41cd64a64381a35b708a4b199825

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08476440B2